Approaches to 2-substituted chroman-4-ones: Synthesis of (-)-pinostrobin

Article abstract of DOI:10.1016/S0040-4039(01)00567-6

Two approaches to optically active 2-substituted chroman-4-ones are described. The first utilized the oxidation of a preformed chroman ring and the second an intramolecular Mitsunobu cyclization. The methodology was applied to the synthesis of the biologically active natural product (-)-pinostrobin (18).

Full text of DOI:10.1016/S0040-4039(01)00567-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3763–3766
Approaches to 2-substituted chroman-4-ones: synthesis of
(−)-pinostrobin
Kevin J. Hodgetts*
Department of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
Received 27 March 2001; accepted 5 April 2001
Abstract—Two approaches to optically active 2-substituted chroman-4-ones are described. The first utilized the oxidation of a
preformed chroman ring and the second an intramolecular Mitsunobu cyclization. The methodology was applied to the synthesis
of the biologically active natural product (−)-pinostrobin (18). © 2001 Elsevier Science Ltd. All rights reserved.
2-Substituted chroman-4-ones are widely distributed in
nature and many show significant biological activity.1
The preparation of 2-substituted chroman-4-ones can
be problematic due to the ease with which they undergo
ring-opening to the chalcone.2 Stereocontrolled routes
to these compounds are therefore limited in number.
Successful examples include the diastereoselective con-
jugate addition of cuprates to homochiral 3-(p-tolyl-
sulfinyl)chromanones3 and an approach based on the
Houben–Hoesch reaction.4 The synthesis of related 2-
substituted chromans,5 chromenes6 and chromanols7
has also been reported. We recently described a general
two-step synthesis of the 2-substituted chroman ring
system based on an intermolecular Mitsunobu reaction
between 2-bromophenol (1) and readily available chiral
halopropanols 2, followed by cyclization to the chro-
man 4 (Scheme 1).8 In this communication we wish to
describe the investigation into the oxidation of chiral
2-substituted chromans to the corresponding chroman-
4-ones and an alternative route based on an intramolec-
ular Mitsunobu reaction.
phenylchroman (4a)9 was subjected to the standard
conditions (Table 1, entry 1).10 The chroman-4-one 5a
was the major product (43% yield) but a substantial
amount of the quinone 6a11 was also produced. The
quinone 6a was presumably formed by competing oxi-
dation at the chroman-2-position of 4a, ring-opening to
the phenol and finally oxidation. Replacement of the
2-phenyl group by a 2-methyl group gave an increased
yield of the chroman-4-one 5b, although a significant
amount of the quinone 6b was also produced under the
reaction conditions (entry 2). In view of the susceptibil-
ity for oxidation at the 2-position, a milder oxidizing
system was sought. Treatment of 4a with two equiva-
lents of copper sulfate and 20 mol% peroxydisulfate12
in aqueous acetonitrile at 65°C gave three products
(entry 3). The major product was the chroman-4-one 5a
accompanied by the known benzylic alcohols 7a and
8a.13 Under these conditions, none of the quinone 6a
was observed. Re-subjecting the mixture to the reaction
conditions or using a larger excess of the reagents
(entry 4) gave complete oxidation to (2S)-(−)-
phenylchroman-4-one (5a) in 43% isolated yield ([h]D=
−66 (c=1 in CHCl3) [lit.14 [h]D=−64.4 (c=0.35 in
CHCl3)]). Under the same conditions oxidation of
The chromium(VI) oxide catalyzed benzylic oxidation
with periodic acid was recently reported and (2S)-(−)-
n
Scheme 1. Reaction conditions: (i) PPh3, DEAD, THF, 64–85%; (ii) BuLi, THF, −50°C to rt, 74–83%.
* Corresponding author. Present address: Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405, USA. Tel.: 1-203-488-8201;
fax: 1-203-483-7027; e-mail: khodgetts@nrgn.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00567-6

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K. J. Hodgetts / Tetrahedron Letters 42 (2001) 3763–3766
Table 1. Oxidation of chroman 4
Entry
R
Conditions
Ratio 5:6:7:8a
Yield 5 (%)b
1
2
3
4
5
6
7
Ph
Me
Ph
Ph
Me
Ph
(i)
(i)
57:43:0:0
75:25:0:0
75:0:19:6
5a only
5b only
5a only
5b only
43
53
35
43
51
39
42
(ii)
(iii)
(iii)
(iv)
(iv)
Me
Reaction conditions: (i) H5IO6, CrO3 (cat.), CH3CN, rt; (ii) CuSO4 (2 mol equiv.), K2S2O8 (0.2 mol equiv.), CH3CN, H2O, 65°C; (iii) CuSO4 (4
mol equiv.), K2S2O8 (0.4 mol equiv.), CH3CN, H2O, 65°C; (iv) CAN, AcOH, H2O, 95°C.
a Determined by 1H NMR (400 MHz) analysis of the crude reaction mixture.
b Isolated yield.
(2R)-(+)-methylchroman (4b) gave (2R)-(+)-methyl-
chroman-4-one (5b) in 51% isolated yield ([h]D=+51
(c=1 in CHCl3) [for the (2S)-enantiomer lit.3a [h]D=
−50 (c=1.2 in CHCl3)]). The magnitude of rotation of
5a and 5b indicated that the oxidation had proceeded
without significant racemization. The use of cerium
ammonium nitrate in aqueous acetic acid gave very
similar results although the isolated yields of 5a and 5b
were slightly reduced (entries 6 and 7).15 The moderate
isolated yields in the oxidation step, however, prompted
the investigation of an alternative route to 2-substituted
chroman-4-ones.
2).18 Addition of two equivalents of lithium o-
lithiumphenoxide19 (prepared from 2-bromophenol and
two equivalents nBuLi) to the amide 10a gave the
ketone 11a in 85% yield (based on 10a). The TBS group
was removed by treatment with 10% p-TsOH in
aqueous THF and gave 12a in 83% yield. Treatment of
12a with triphenylphosphine (1 equiv.) and diethyl
azodicarboxylate (DEAD) (1 equiv.) in THF at 0°C
resulted in smooth cyclization to the chromanone 5a in
86% yield ([h]D=−67 (c=1 in CHCl3) [lit.14 [h]D=−
64.4 (c=0.35 in CHCl3)]).20 A minor by-product was
identified as the elimination product 13a which was
isolated in 5% yield. Several groups have used an
intramolecular Mitsunobu reaction to prepare six- and
seven-membered cyclic ethers,21 but we believe this to
be the first example of the formation of an optically
active chroman-4-one via this approach. Repeating the
sequence with ethyl (S)-(+)-3-hydroxybutyrate (9b)
gave (2R)-(+)-methylchroman-4-one (5b) in excellent
Optically active b-hydroxy esters are readily available,
either commercially or via asymmetric hydrogenation
of the appropriate b-keto ester.16 Commercially avail-
able (+)-ethyl (R)-3-hydroxy-3-phenylpropanoate (9a)17
was protected as its TBS ether and converted into the
Weinreb amide 10a under standard conditions (Scheme
Scheme 2. Reaction conditions: (i) TBSCl, imidazole, CH2Cl2 (93%); (ii) MeONHMe·HCl, Me3Al, CH2Cl2, (82%); (iii) 2-
n
bromophenol (2 equiv.), BuLi, ether, −78°C to rt; (85%); (iv) p-TsOH (10%), THF/H2O (9:1), 55°C (83%); (v) PPh3, DEAD,
THF, 0°C (86%).

K. J. Hodgetts / Tetrahedron Letters 42 (2001) 3763–3766
3765
t
Scheme 3. Reaction conditions: (i) BuLi, PhMe, −78°C then 10a (0.5 equiv.) (72%); (ii) p-TsOH (10%), THF/H2O (9:1), 55°C
(86%); (iii) PPh3, DEAD, THF, 0°C (88%); (iv) AlCl3, CH3CN, reflux (79%).
overall yield ([h]D=+51 (c=1 in CHCl3) [for the (2S)-
enantiomer lit.3a [h]D=−50 (c=1.2 in CHCl3)]).
under the Newman Fellowship program. John Hill
(Kent mass spectrometry) is thanked for mass spectra
and Robertson analytical for elemental analysis and
optical polarimetry.
Pinostrobin (18) has been isolated from several natural
sources22 and shown to inhibit aromatase, a cytochrome
P450 enzyme converting C19 androgens such as
androstenedione to estrone and testosterone to estra-
diol.23 This mode of action could prevent the develop-
ment of estrogen related tumors such as breast and
prostate cancer.24 In addition, pinostrobin (18) has been
isolated from T. graveolens, a plant used in traditional
Mexican medicine for the treatment of gastrointestinal
ailments such as diarrhoea and stomach pain.25 It was
recently demonstrated that pinostrobin (18) was an
active ingredient in T. graveolens and inhibited intestinal
smooth muscle contractions by a calcium-mediated
mechanism.26 The interesting biological activity makes
pinostrobin an attractive target for synthesis. Under
standard conditions, 3,5- dimethoxyphenol was pro-
tected as the MOM ether 14 and following o-lithiation,
treated with the amide 10a (Scheme 3). Under these
conditions ketone 15 was isolated in 72% yield. The
protecting groups on 15 were conveniently cleaved by
treatment with 10% p-TsOH in aqueous THF which
gave the cyclization precursor 16. Intramolecular Mit-
sunobu cyclization of 16 gave an 88% yield of
dimethylpinocembrin (17).27 Regioselective demethyla-
tion of 17 with aluminum chloride3b gave, following
chromatography, (−)-pinostrobin (18) ([h]D=−48 (c=1
in CHCl3) [lit.22a [h]D=−52.7 (c=1 in CHCl3)].
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